A chiral 2,3,4-trisubstituted pyrrolidine glycosidase inhibitor has been obtained from 1-hydroxymethyl-4-sulfonylbutadiene.As part of a program seeking to exploit the reactivity of 1-hydroxymethyl-4-sulfonylbutadienes in the synthesis of oxygen and nitrogen heterocycles we have prepared a chiral 2,3,4-trisubstituted pyrrolidine, 9, recently synthesized by several groups for its glycosidase inhibitor activity. 1 1,3-dienes with a sulfone or sulfoxide group have been the object of study of many research groups in recent years. 2 In our case we want to exploit the presence of an allylic alcohol that opens the door to enantioselective syntheses.The versatility of this kind of compound is illustrated in Scheme 1.
Scheme 1In previous work we have reported the synthesis of isosorbide analogues that exploit the chemo-and enantioselective epoxidation of a sulfonylbutadiene and the reactivity towards electrophiles of the a position of the resultant vinyl sulfone. 3 In the work reported in this paper we wished to investigate the possibility of performing, in a one pot reaction, an S N2 displacement at an appropriately activated hydroxymethyl group and a Michael addition to the vinyl sulfone. With a nitrogen nucleophile, this methodology was expected to give pyrrolidines in chiral form, the enantiomer being accessed depending upon the Sharpless conditions. The presence of these pyrrolidines in natural and pharmaceutical products with interesting biological activities, 1,4 and their use as conformationally constrained amino acid analogues 4b , makes them interesting targets, and this procedure provides a versatile method for their synthesis. The retrosynthetic analysis for 9 is shown in Scheme 2.
Scheme 2As can be appreciated, the trans stereochemistry in the D 2 double bond of 1 will lead to the trans epoxide and thus frustrate any attempt at direct cyclization of 2 or derivatives such as 3. It is necessary to change this configuration in order to produce the required ring. This was done by the Wershofen-Scharf procedure 5 -treatment of the tosyl epoxide 3 with AlCl 3 in acetone -which in one step gave the required stereochemistry and protection of the two hydroxy groups (Scheme 3).Scheme 3 a) Sharpless, L(+)-DET, 85%; b) TsCl, Py., 80%; c) AlCl 3 , acetone, 65%; d) BnNH 2 , MeOH, Et 3 N, 78%; e) H 2 , Pd/C, MeOH, 95% Downloaded by: East Carolina University. Copyrighted material.
